This invention relates to a novel class of compounds which exhibit analgesic activity.
Recently, endogenous substances having morphine-like properties have been extracted from mammalian brain or csf. These substances, named enkephalin, have been identified by Hughes et al., Nature, 258, 577 (1975) as pentapeptides having the following sequences: EQU H-Tyr-Gly-Gly-Phe-Met-OH EQU H-Tyr-Gly-Gly-Phe-Leu-OH.
These compounds are referred to as methionine-enkephalin and leucine-enkephalin, respectively.
Although methionine and leucine enkephalin have been shown to exhibit analgesic activity in mice upon administration intracerebroventricularly [Buscher et al., Nature, 261, 423 (1976)], they are practically devoid of any useful analgesic activity when administered parenterally.
Therefore, since the discovery of the enkephalins, much effort has been devoted to preparing analogs of the enkephalins in the hope of finding compounds having enhanced activity and practical utility due to their bioavailability by parenteral or oral administration.
Dutta et al., Life Sciences 21, pp. 559-562 (1977) report certain structure modifications which, they suggest, tend to enhance potency. They suggest activity can be enhanced by any or all of the following:
(a) substitution of Gly in position 2 by certain D- or .alpha.-aza-amino acids; PA1 (b) conversion of the terminal carboxyl to the methyl ester or the amide; PA1 (c) modification of the Phe in the 4-position by .alpha.-aza substitution, N-methylation, or hydrogenation of the aromatic ring. PA1 R.sub.1 is hydrogen or C.sub.1 -C.sub.3 primary alkyl; PA1 R.sub.2 is C.sub.1 -C.sub.4 primary or secondary alkyl, allyl, cyclopropylmethyl, C.sub.1 -C.sub.2 hydroxyalkyl, or --(CH.sub.2).sub.m -U-CH.sub.3 in which U is --S-- or ##STR6## and m is 1 or 2; R.sub.3 is hydrogen, C.sub.1 -C.sub.4 primary or secondary alkyl, cyclopropylmethyl, or allyl; PA1 R.sub.4 is hydrogen, C.sub.1 -C.sub.5 primary or secondary alkyl, --(CH.sub.2).sub.n -X-(CH.sub.2).sub.p --CH.sub.3 in which X is --O--, --S--, ##STR7## n is 1 or 2, and p is 0 or 1, phenyl, or monosubstituted phenyl in which the substituent is halo, hydroxy, C.sub.1 -C.sub.3 alkoxy, nitro, C.sub.1 -C.sub.3 alkyl, or trifluoromethyl; PA1 R.sub.5 is hydrogen or C.sub.1 -C.sub.4 primary alkyl; and PA1 Z is --CH.sub.2 OR.sub.6, ##STR8## in which R.sub.6 is hydrogen or C.sub.1 -C.sub.3 alkyl and R.sub.7 is C.sub.1 -C.sub.3 alkyl; PA1 Abu: .alpha.-aminobutyric acid PA1 Ahp: .alpha.-aminoheptanoic acid PA1 Ala: alanine PA1 Cys: cysteine PA1 Cys(Et): (S-ethyl)cysteine PA1 Cys(Et): (O) (S-ethyl)cysteine sulfoxide PA1 Cys(Et): (O.sub.2) (S-ethyl)cysteine sulfone PA1 Cys(Me): (S-methyl)cysteine PA1 Cys(Me) (O): (S-methyl)cysteine sulfoxide PA1 Cys(Me) (O.sub.2): (S-methyl)cysteine sulfone PA1 Eth: ethionine PA1 Eth(O): ethionine sulfoxide PA1 Eth(O.sub.2): ethionine sulfone PA1 Gly: glycine PA1 Gly(Al): allylglycine PA1 Gly(Cp): cyclopropylmethylglycine PA1 Hil: homoisoleucine PA1 Hle: homoleucine PA1 Hse: homoserine PA1 Hse(Me): (O-methyl)homoserine PA1 Hse(Et): (O-ethyl)homoserine PA1 Ile: isoleucine PA1 Leu: leucine PA1 Met: methionine PA1 Met(O): methionine sulfoxide PA1 Met(O.sub.2): methionine sulfone PA1 Nle: norleucine PA1 Npg: neopentylglycine PA1 Nva: norvaline PA1 Pgl: phenylglycine PA1 Pgl(OH): p-hydroxyphenylglycine PA1 Phe: phenylalanine PA1 Phe(F): p-fluorophenylalanine PA1 Ser: serine PA1 Ser(Me): (O-methyl)serine PA1 Ser(Et): (O-ethyl)serine PA1 Thr: threonine PA1 Tyr: tyrosine PA1 Val: valine PA1 Ac: acetyl PA1 Al: allyl PA1 Cp: cyclopropylmethyl PA1 Me: methyl PA1 Et: ethyl PA1 Ip: isopropyl PA1 Pr: n-propyl PA1 Bu: n-butyl PA1 i-Bu: isobutyl PA1 t-Bu: t-butyl PA1 s-Bu: sec-butyl PA1 Boc: t-butyloxycarbonyl PA1 Bzl: benzyl PA1 Cbz: benzyloxycarbonyl PA1 DCC: N,N'-dicyclohexylcarbodiimide PA1 HBT: 1-hydroxybenzotriazole PA1 DMF: N,N-dimethylformamide PA1 TFA: trifluoroacetic acid PA1 THF: tetrahydrofuran PA1 DEAE: diethylaminoethyl PA1 IBCF: isobutyl chloroformate PA1 NMM: N-methylmorpholine PA1 18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane
In addition, Roemer et al., Nature 268, pp. 547-549 (1977), suggest modification of the Met.sup.5 to its corresponding carbinol and oxidation of the Met sulfur to the sulfoxide as useful modifications.
Another structure modification of significance is that reported in Belgian Pat. No. 859,026. This publication suggests enhancement of activity and bioavailability of enkephalin analogs by insertion of a D-amino acid residue in position 2, conversion of the terminal carboxyl to an amide, and N-alkylation of the amino acid residue in position 5.
A class of analogs of enkephalin having a high level of analgesic activity has now been discovered. These analogs are halogenated enkephalins which are structurally highly specific in terms both of the identity and the position of the halogen. The compounds of this invention are pentapeptides having the residue of a p-fluoro-substituted L-phenylalanine in the 4-position of the peptide.
The literature recognizes other halogenated 4-phenylalanyl enkephalin analogs; however, none are mono p-fluoro-substituted 4-phenylalanyl enkephalin analogs. A. R. Day et al., Res. Comm. in Chem. Path. and Pharmacol. 14 (4), 597-603 (1976) reports H-Tyr-Gly-Gly-pClPhe-Nle-OH. R. J. Miller et al., Vitamins and Hormones 36, 297-382, Academic Press (1978) mentions H-Tyr-D-Ala-Gly-pClPhe-D-Leu-OH; H-Tyr-D-Ala-Gly-pClPhe-D-Leu-OMe; and H-Tyr-D-Ala-Gly-pClPhe-D-Leu-NHEt. Pless et al., "Opioid Activity of Enkephalin Analogues," presented at the 15th European Peptide Symposium, Sept. 4-9, 1978, Gdansk, Poland, reports H-Tyr-D-Ala-Gly-pClPhe-Met(O)-OL. D. H. Coy et al., BBRC 83 (3), 977-983 (1978) mentions H-Tyr-D-Ala-Gly-F.sub.5 -Phe-Met-NH.sub.2.
None of the above reports the compounds of this invention, and it has been discovered that both the identity and position of the halogen play a significant role in the level of analgesic activity of the enkephalin analog.